Phenylacetic Acid, a Gut Microbially Produced Metabolite, Reduces Atherosclerosis Burden and Impacts Host Lipid Homeostasis

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BACKGROUND: Gut microbial metabolism of dietary phenylalanine produces phenylacetic acid (PAA), followed by the host conversion to phenylacetylglutamine in humans and phenylacetylglycine in mice. Phenylacetylglutamine was linked to cardiovascular disease risk in multiple clinical studies, yet whether the microbial pathways leading to PAA/phenylacetylglutamine/phenylacetylglycine formation influence atherosclerosis progression within the host remains elusive. METHODS: mice on a Western diet were provided with a gut microbial metabolite PAA to investigate its effects on host cardiometabolic health. RESULTS: Circulating levels of phenylacetylglutamine and phenylacetylglycine were increased by the treatment without affecting circulating cholesterol or inflammatory cytokines. In male mice, PAA elevated triglycerides and fasting glucose. PAA decreased the total atherosclerotic plaque burden within the descending and abdominal aortas of both sexes and within brachiocephalic arteries in male mice without affecting plaque stability indices. PAA altered gut microbial composition but did not markedly shift production of established atherosclerosis-related microbial metabolites, aside from a modest rise in indoxyl sulfate in female mice. Furthermore, PAA treatment decreased circulating levels of acyl- and free carnitines through reduced availability of their biosynthetic precursors and upregulated expression of genes involved in peroxisomal lipid metabolism. CONCLUSIONS: These results offer new insights into the impact of gut-microbial metabolism of phenylalanine on host metabolism and atherosclerosis progression. Our findings suggest that clinical associations between phenylacetylglutamine and cardiovascular disease risk are unlikely to be driven by increased atherosclerosis.

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